Imaging immunity in patients with cancer using positron emission tomography

Abstract

Immune checkpoint inhibitors and related molecules can achieve tumour regression, and even prolonged survival, for a subset of cancer patients with an otherwise dire prognosis. However, it remains unclear why some patients respond to immunotherapy and others do not. PET imaging has the potential to characterise the spatial and temporal heterogeneity of both immunotherapy target molecules and the tumor immune microenvironment, suggesting a tantalising vision of personally-adapted immunomodulatory treatment regimens. Personalised combinations of immunotherapy with local therapies and other systemic therapies, would be informed by immune imaging and subsequently modified in accordance with therapeutically induced immune environmental changes. An ideal PET imaging biomarker would facilitate the choice of initial therapy and would permit sequential imaging in time-frames that could provide actionable information to guide subsequent therapy. Such imaging should provide either prognostic or predictive measures of responsiveness relevant to key immunotherapy types but, most importantly, guide key decisions on initiation, continuation, change or cessation of treatment to reduce the cost and morbidity of treatment while enhancing survival outcomes. We survey the current literature, focusing on clinically relevant immune checkpoint immunotherapies, for which novel PET tracers are being developed, and discuss what steps are needed to make this vision a reality.

Fig. 1. Immune activation imaged by FDG-PET.

FDG-PET/CT images of a patient FDG-avid left axillary lymphadenopathy after COVID-19 vaccination, reflecting glucose metabolism in immune cells. In the maximum intensity projection image (panel A), lymph nodes appear as black spots and in the transverse PET/CT image (panel B) as light green regions.

Fig. 2. The patient journey: PET in precision medicine.

After the diagnosis has been established, PET will help select the optimal treatment to the patient. During the course of the treatment, several questions may arise, which cannot be solved by IRECIST. Here, PET may be indicated to answer specific questions.

Fig. 3. Imaging PD-L1 in xenograft models and in a human subject using ⁸⁹Zr-DFO-Sq-Durvalumab PET/CT.

The upper panels show ⁸⁹Zr-DFO-Sq -Durvalumab PET/CT imaging of NSG mouse bearing either HCC-827 PD-L1 high tumour (Panel A) or a low-to-non PD-L1 expressing A549 tumour (Panel B) at 144 h after PET tracer injection. Pseudo-coloured SUV overlays on CT scan maximum projection images are shown. Subcutaneous human tumour xenografts on right flanks are indicated by arrows. The lower panels show the same ⁸⁹Zr-durvalumab, as validated in the xenograft model, used for PET/CT imaging in a human subject with PD-L1 positive (90%) stage IV NSCLC. Over 6 days, sequential images show gradual accumulation of tracer in distant metastases. Axial PET/CT images (upper panels) show increasingly intensification of uptake in a vertebral body metastasis. Maximum intensity projection (MIP) images (lower panels) show blood pool imaging (day 1) and then gradual accumulation in metastatic disease, including lumbar spine and left hip. (Images courtesy of Dr Tim Akhurst, Peter MacCallum Cancer Centre).

Fig. 4. Development of a putative novel tracer.

Novel tracer development of a putative CD8 tracer, based on small-antibody alternatives, which could then be integrated with existing tracers to image activated CD-8 cells, such as ¹⁸F- arabino-furanosylguanine (ARA-G). Combination studies with T-cell tracers and tracers for PD-L1/PD-1 such as adnectin ¹⁸F-18F-BMS-986192 could help determine the causes of immunotherapy resistance in patients on ICI, as well as being used to investigate the mechanisms of therapeutic strategies such as induction of abscopal effects after radiotherapy.

Fig. 5. Imaging activated CD8 T cells with ¹⁸F-AraG.

Baseline imaging a patient with recurrent malignant melanoma, scanned at 60 min after IV injection of approximately 185 MBq of ¹⁸F-AraG prior to immune check-point therapy. A Maximum intensity projection (MIP) image demonstrates uptake in inguinal nodal disease (Blue arrows) and in transit nodules (Green arrows). Panel (A): Fused PET/CT and coronal PET images demonstrate moderately intense uptake in the pituitary, salivary glands, myocardium, liver and pancreas. All these organs are subject to immune-related adverse events and how this biodistribution will impact diagnostic performance is unclear. Panel (B): Increased uptake is observed in two inguinal lymph nodes, with associated nodal enlargement of the upper node. Panel (C): The small lower in transit nodule is clearly identified on both PET and correlative CT (Image provided by Dr Diwakar Davar and Dr Shyam Srinivas from University of Pennsylvania Medical Center and Dr Jelena Levi of CellSight).